Molecular Medicine最新文献

{"title":"Gut dysbiosis modulates hyperoxia-induced bronchopulmonary dysplasia by promoting EMT through activating TLR4/NF-κB pathway.","authors":"Yaqin Yan, Shuling Liang, Sen Li, Shunv Xie, Xiaohui Wang, Huayan Zhang","doi":"10.1186/s10020-026-01529-x","DOIUrl":"10.1186/s10020-026-01529-x","url":null,"abstract":"<p><strong>Background: </strong>Bronchopulmonary dysplasia (BPD) is a major cause of morbidity and mortality in premature infants. Although gut microbial dysbiosis is implicated in BPD pathogenesis, the underlying mechanisms are poorly defined. This study aims to elucidate the specific pathway through which gut dysbiosis drives BPD pathology and to identify potential therapeutic targets.</p><p><strong>Methods: </strong>The experimental BPD model was established by hyperoxia (FiO₂ 85%) in neonatal mice from postnatal days 1 to 14. Pulmonary alveolarization and inflammation were analyzed at postnatal day 15. The modulatory role of gut microbiota was assessed using antibiotic-induced dysbiosis and fecal microbiota transplantation (FMT) from normoxic mice. Gut microbiome analysis was performed using 16S rRNA gene sequencing. The specific signaling pathway was investigated using a pharmacological inhibitor of TLR4. Furthermore, the molecular mechanisms were investigated through western blotting, real-time quantitative PCR, ELISA, and immunofluorescence.</p><p><strong>Results: </strong>Hyperoxia exposure induced impaired alveolarization, disrupted gut barrier integrity, and gut dysbiosis. These pathological changes were accompanied by elevated pulmonary inflammation, potent activation of the TLR4/NF-κB pathway, and upregulation of epithelial-mesenchymal transition (EMT) associated markers. These changes were exacerbated by early postnatal antibiotic administration, whereas FMT from normoxic mice rescued these phenotypes, restored gut barrier function, suppressed TLR4/NF-κB signaling, and reversed EMT progression. Notably, pharmacological inhibition of TLR4 mirrored the protective effects of FMT, effectively attenuating hyperoxia-induced lung injury and EMT.</p><p><strong>Conclusions: </strong>Our findings establish a mechanistic link for the gut-lung axis in BPD, demonstrating that gut dysbiosis is a critical modulator of lung development impairment and pathological EMT via activation of the TLR4/NF-κB pathway.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic variants in IGF2BP family genes are associated with glioma risk in Chinese children.","authors":"Yuling Su, Yuxiang Liao, Li Yuan, Linqian Wang, Jiabin Liu, Haixia Zhou, Tianyou Wang, Jing He","doi":"10.1186/s10020-026-01527-z","DOIUrl":"10.1186/s10020-026-01527-z","url":null,"abstract":"<p><strong>Background: </strong>Glioma is a highly prevalent malignant tumor of the central nervous system in children and is driven by complex genetic and environmental factors. IGF2BP family genes (IGF2BP1, IGF2BP2, and IGF2BP3) encode critical RNA epigenetic \"readers\" that participate in posttranscriptional gene regulation and modulate various cellular processes. However, the contributions of these gene variants to glioma risk remain unclear.</p><p><strong>Methods: </strong>A multicenter case-control study was conducted, enrolling 360 patients with glioma and 547 cancer-free controls. Genotyping of 11 potentially functional polymorphisms within IGF2BP family genes was performed using the TaqMan assay. Unconditional logistic regression models were employed to estimate odds ratios and 95% confidence intervals. Furthermore, expression quantitative trait loci (eQTL) and The Cancer Genome Atlas (TCGA) clinical database analyses were conducted to investigate the potential regulatory mechanisms and clinical significance of the identified variants.</p><p><strong>Results: </strong>We found that the IGF2BP1 rs2270575 polymorphism was significantly associated with a decreased risk of glioma. Conversely, the IGF2BP2 rs17289925 and rs7646419 polymorphisms were linked to increased glioma risk. Stratification and cumulative effect analyses revealed that harboring multiple risk genotypes of IGF2BP1 or IGF2BP2 substantially increased glioma susceptibility. This cumulative risk was especially notable among males, younger children (< 60 months), and patients diagnosed with early-stage (I + II) tumors. Additionally, eQTL and TCGA analyses revealed that the rs2270575 and rs7646419 alleles correlated significantly with altered mRNA expression levels of CALCOCO2 and AC099661.1 (ENSG00000286086), respectively, which further correlated with favorable molecular subtypes (IDH mutation status) and WHO tumor grades.</p><p><strong>Conclusion: </strong>Genetic polymorphisms within IGF2BP family genes significantly modulate pediatric glioma susceptibility and have cumulative, subtype-specific, and age-dependent effects; thus, these genes may serve as promising noninvasive biomarkers for early risk stratification of childhood glioma.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Adrenergic receptors as immunomodulators in T cells: mechanisms of neuroimmune crosstalk and pathophysiological implications.","authors":"Junyan Yao, Suli Zhang, Fei Sun, Mingyang Chen, Huirong Liu","doi":"10.1186/s10020-026-01526-0","DOIUrl":"10.1186/s10020-026-01526-0","url":null,"abstract":"<p><p>Regulation of T cell function by the sympathetic nervous system via β-adrenergic receptors is a pivotal research focus in neuroimmunology, with most studies centered on β₂-adrenergic receptors. However, the roles of other subtypes remain unclear. This review systematically summarizes differential expression and signaling of β₂- and β₁-adrenergic receptors across T cell subsets. While β₂-adrenergic receptor bidirectionally modulates immune responsiveness through classical or non-classical pathways, β₁-adrenergic receptor is predominantly expressed in regulatory and exhausted T cells, exerting immunosuppression via the cAMP-CREM axis. Furthermore, this review examines the pathophysiological roles of β-adrenergic receptor signaling in the tumor immune microenvironment, autoimmune diseases, infections and cardiovascular diseases, highlighting β₁-adrenergic receptor as a candidate immune checkpoint. Ultimately, elucidating the subtype-specific mechanisms of β-adrenergic signaling provides a critical framework for understanding immune dysregulation and highlights the potential of targeting these pathways to restore immune homeostasis in various pathological contexts.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Formyl peptide receptor 1 agonism selectively suppresses mitochondria-driven neutrophil extracellular trap formation while preserving antibacterial immunity.","authors":"Emil Bečka, Letícia Hudecová, Patrik Bertovič, Karolína Bíla, Ľudmila Podracká, Peter Celec, Michal Pastorek","doi":"10.1186/s10020-026-01522-4","DOIUrl":"10.1186/s10020-026-01522-4","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial damage-associated molecular patterns (mtDAMPs) released after trauma can trigger neutrophil extracellular trap (NET) formation, potentially worsening tissue injury and increasing susceptibility to secondary infection. However, the mechanisms driving mitochondria-induced NETosis and whether this response can be selectively modulated without impairing antibacterial defense remain unclear.</p><p><strong>Methods: </strong>We investigated the mechanisms of mitochondria-induced NET formation using in vitro, in vivo models and ex vivo, using trauma patient plasma. Neutrophils were exposed to intact mitochondria or mitochondrial components, and the roles of Toll-like receptor 9 (TLR9), formyl peptide receptor 1 (FPR1), PAD4, NOX2, p38α, and STAT6 were assessed. Effect of the synthetic FPR1 agonist FPRA14 on NET formation and antibacterial neutrophil functions was tested in double hit in vivo model of peritoneal mitochondria injection followed by S. aureus pneumonia.</p><p><strong>Results: </strong>Intact mitochondria induced NET formation through coordinated activation of both TLR9 and FPR1, with dependence on PAD4, NOX2, and p38α signaling. Mitochondrial protein integrity was important for this response, likely by protecting mtDNA from degradation and enabling TLR9 activation. While insufficient to drive NETosis alone, FPR1 activation showed a concentration- and time-dependent modulatory effect: low-level activation promoted NETosis, whereas stronger or pre-exposure-induced signaling suppressed it through receptor desensitization. FPR1 agonist FPRA14 reduced mitochondria-driven NET formation in vitro and in a double hit murine model while preserving neutrophil antibacterial functions, including NET formation, phagocytosis, ROS generation, bacterial killing, and infection control. p38α acted as a positive regulator, whereas STAT6 functioned as a negative regulator of NET formation.</p><p><strong>Discussion: </strong>These findings identify FPR1 as a key regulator of pathological mitochondria-driven NETosis and suggest that selective FPR1 receptor desensitization may suppress excessive sterile inflammation without compromising host defense. This work extends current understanding of mtDAMP signaling in neutrophils and supports prophylactic FPR1 agonism as a potential strategy for limiting inflammatory tissue damage after trauma or surgery.</p><p><strong>Conclusion: </strong>Mitochondria-induced NETosis depends on TLR9/FPR1 signaling and can be reduced by FPR1 agonism without compromising antibacterial immunity. FPRA14 may represent a strategy to limit harmful sterile inflammation after trauma or surgery.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of Dymeclin in chronic unpredictable mild stress-induced depression: maintaining the Golgi apparatus structure and regulating NLRP3 inflammasome activation.","authors":"Longfei Du, Zifan Ding, Lei Sun, Ye Qin, Huiling Sun, Yuqin Pan, Shukui Wang","doi":"10.1186/s10020-026-01524-2","DOIUrl":"10.1186/s10020-026-01524-2","url":null,"abstract":"<p><p>The Golgi apparatus plays a key role in innate immune signaling, but its exact role in depression-related neuroinflammation remains unclear. The role of Dymeclin (DYM), a Golgi structural protein, in stress-related psychiatric disorders needs further clarification. This study aims to investigate whether DYM participates in the development of chronic stress-induced depression by regulating Golgi function. A mouse depression model was developed with chronic unpredictable mild stress (CUMS), followed by a rescue experiment using stereotactic injection of DYM-overexpressing lentiviruses into the hippocampus. Depression-associated behaviors, hippocampal metabolites, Golgi apparatus function, and inflammatory markers were examined using mass spectrometry, immunofluorescence, electron microscopy, and immunoprecipitation techniques. Overexpression of DYM mitigated depressive-like behaviors induced by CUMS in mice. Additionally, it enhanced the structural integrity of the Golgi apparatus, suppressed NLRP3 inflammasome activation, reduced levels of central and peripheral inflammatory factors, and partially ameliorated hippocampal metabolic disturbances. In vitro experiments further confirmed that DYM overexpression inhibited LPS-induced NLRP3 upregulation and inflammatory factor release in microglia. This study reveals that chronic stress causes depressive-like behaviors by reducing hippocampal DYM expression, leading to Golgi dysfunction and triggering NLRP3 inflammasome-related neuroinflammation and metabolic issues.This finding broadens the traditional framework of depression research, which has primarily focused on neurons and monoamine neurotransmitters, by underscoring the pivotal role of Golgi organelle homeostasis in mediating the interactions among stress, neuro-immune, and metabolic processes. Our research indicates that targeting the DYM/Golgi pathway could offer new treatment strategies and a theoretical foundation for reducing depression-related neuroinflammation and metabolic issues. Drugs targeting the structural stability of the Golgi apparatus may serve as potential candidates for novel antidepressants in the future.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13488197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial metabolic reprogramming drives diabetic kidney disease progression: cell-specific mechanisms, metabolic memory, and targeted strategies.","authors":"Lingfei Zhang, Yue Zhang, Liu Han, Jialei Wang, Lijie Hou, Songbo Fu","doi":"10.1186/s10020-026-01521-5","DOIUrl":"10.1186/s10020-026-01521-5","url":null,"abstract":"<p><p>Diabetic Kidney Disease (DKD), as a major microvascular complication of diabetes, is the leading cause of chronic kidney disease and end-stage kidney disease. Metabolic reprogramming is an important concept in cancer research, and the most classic example is the Warburg effect. This phenomenon has also been observed in DKD, suggesting that metabolic reprogramming also plays a significant role in DKD. Mitochondria are crucial in both catabolism and anabolism, making them the center of metabolic reprogramming research. Additionally, mitochondria are involved in methylation and acetylation modifications, potentially playing a vital role in \"metabolic memory.\" Starting from the metabolic landscape of mitochondria in cells, this review discusses mitochondrial metabolic reprogramming in different types of renal and immune cells, providing insights into the mechanisms underlying \"metabolic memory.\" In addition, we comprehensively summarize therapeutic strategies targeting mitochondrial metabolic reprogramming from both preclinical and clinical perspectives. Unlike previous studies that primarily focused on individual pathophysiological processes, this review integrates the intrinsic link between mitochondrial metabolic reprogramming and epigenetic modifications associated with \"metabolic memory,\" thereby offering a novel interdisciplinary perspective for overcoming current therapeutic bottlenecks in DKD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148218442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A peptide-induced regression of low-grade malignant breast tumor via activation of autophagy in breast cancer cells.","authors":"Saibal Saha, Rishikesh Kumar, Snehanjan Sarangi, Animesh Gope, Ananda Pal, Rima Tapader, Niraj Nag, Sushmita Bhattacharya, Amit Pal","doi":"10.1186/s10020-026-01514-4","DOIUrl":"10.1186/s10020-026-01514-4","url":null,"abstract":"<p><p>Peptides have recently gained much attention for their therapeutic role in several diseases without having significant side effects. These are short chain amino acids and can be synthesized chemically with a great extent of purity, which renders them very effective, precise and safe for the body. So far, very few artificially synthesized peptides have been developed that have autophagy-inducing properties. Among them, a very small number of peptides have been demonstrated to have anti-tumorigenic effect by modulating autophagy with most of them lacking specificity for target cells. This study aims to investigate the regulation of autophagy through noncanonical activation of protease-activated receptor 1 (PAR1) by hemagglutinin protease (HAP). Unlike the canonical activation of PAR1 by thrombin, which enhances cell proliferation via mechanistic target of rapamycin (mTOR) signaling, HAP-induced noncanonical activation downregulates mTOR activation and triggers autophagy in both estrogen receptor positive/ progesterone receptor positive/ HER2 negative (ER+/PR+/HER2-) and triple negative (ER-/PR-/HER2-) breast cancer cells. This noncanonical activation generates a N-terminal sequence in PAR1. When this sequence is mimicked by a synthetic peptide, it induces autophagy independently of HAP in the breast cancer cells in vitro. Further in vivo investigation in BALB/c mouse model of low-grade malignant breast tumor reveals that the peptide-induced autophagy significantly inhibits tumor growth and delays tumor progression. Importantly, the lack of PAR1 expression in normal, healthy breast epithelial cells facilitates the peptide to selectively target breast cancer cells with relatively high PAR1 expression, highlighting its potential as a therapeutic agent against low-grade malignant breast tumor. These findings provide valuable insights into autophagy activation by a synthetic peptide that targets breast cancer cells with high PAR1 expression and for the first time shows peptide mediated targeted therapy of low-grade malignant breast tumor.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148211965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Calcium Uniporter protects hippocampal CA2 neurons from NMDA-induced excitotoxic injury.","authors":"Aleksandra Skweres, Małgorzata Beręsewicz-Haller, Omar Basheer, Martyna Nalepa, Aleksandra Owczarek, Jakub Szymanowski, Maria Kawalec, Joanna Gruszczyńska-Biegała, Barbara Zabłocka, Michał Węgrzynowicz","doi":"10.1186/s10020-026-01528-y","DOIUrl":"10.1186/s10020-026-01528-y","url":null,"abstract":"<p><strong>Background: </strong>The hippocampal region CA2, unlike neighboring CA1, is exceptionally resistant to excitotoxicity, although the mechanisms behind this phenotype are unknown. Given the importance of mitochondrial calcium buffering, we investigated whether Mitochondrial Calcium Uniporter (MCU), known to be enriched in CA2, contributes to this resistance.</p><p><strong>Methods: </strong>We employed immunostaining techniques in rodent brain tissue and organotypic slice cultures to visualize MCU across hippocampal regions under resting and excitotoxic conditions. Subsequently, we pharmacologically modulated MCU in an organotypic model of hippocampal excitotoxicity to assess its contribution to regional resistance.</p><p><strong>Results: </strong>We found a strong spatial correlation between resistance to NMDA excitotoxic injury and MCU expression. NMDA exposure resulted in MCU upregulation in CA2, and pharmacological inhibition of MCU sensitized CA2 neurons to excitotoxic damage in a dose-dependent manner, while having minimal effect on the already vulnerable CA1 neurons, which express low MCU levels.</p><p><strong>Conclusions: </strong>MCU is known to exacerbate NMDA-induced cell injury, although our data demonstrate a functional association between MCU activity and CA2 neuroprotection, suggesting that CA2 neurons may possess unique mitochondrial calcium handling capabilities. Our study provides novel insight into mechanisms supporting CA2 resistance to NMDA excitotoxic death and emphasizes context-dependent roles of MCU in neuronal injury or survival.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Molecular mechanisms of α-syn abnormal phase separation in cognitive impairment induced by chronic intermittent hypoxia and the neuroprotective effects of Danshensu methyl ester.","authors":"Juan Li, Na Zhang, Ziyin Zhang, Jinsai Fu, Wenjing Ren, Yi Sun, Shuling Song, Xiaoqian Liu, Jinghui Liu, Jingyu Wang, Yunliang Sun, Kai Zhang, Rongrong Guo, Changjun Lv, Lei Pan, Guiwu Qu, Fang Han, Yan Yu","doi":"10.1186/s10020-026-01519-z","DOIUrl":"10.1186/s10020-026-01519-z","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13245082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic lethality between PBRM1 deficiency and PARP inhibitors: exploiting G2/M checkpoint arrest in colorectal cancer.","authors":"Mohd Tarequl Islam, Haiwei Quan, Shuangquan Chen, Zhiguang Xu, Mingzhou Guo, Zhibin Wang","doi":"10.1186/s10020-026-01525-1","DOIUrl":"10.1186/s10020-026-01525-1","url":null,"abstract":"<p><strong>Background: </strong>Polybromo 1 (PBRM1), encoding the BAF180 subunit of the polybromo-associated BAF (PBAF) chromatin-remodeling complex, is commonly lost or mutated across malignancies. Despite its prevalence, tailored therapeutics for PBRM1-defective cancers remain limited. PBRM1 loss is associated with elevated replication stress and DNA damage responses, implying dependence on compensatory repair pathways. Given the lack of genotype-matched drugs, exploiting DNA-repair dependencies may provide a precision option for PBRM1-deficient disease. We pursued a synthetic-lethality strategy in colorectal cancer to test whether clinically used PARP inhibitors selectively suppress PBRM1-deficient cells and to define the linked cell-cycle and stress-response mechanisms. We also compared PARP inhibition with broader chromatin-remodeler targeting.</p><p><strong>Methods: </strong>Isogenic PBRM1^-/- HCT116 colorectal carcinoma cells were generated by CRISPR/Cas9 lentiviral editing using sgRNAs cloned into lenti-CRISPR-V2. Knockout was confirmed by Western blotting, Sanger sequencing, and RT-qPCR. A focused compound screen compared four agents PARP inhibitors olaparib and rucaparib, the multi-target chromatin remodeler inhibitor AU-24,118, and the SMARCA2/4-targeting degrader AU-1530 using dose-response CCK-8 viability assays and selectivity indices. We then validated our results by 12-day colony-formation assays. Mechanistic analyses measured drug-induced G2/M accumulation by propidium iodide staining and flow cytometry and quantified apoptosis by Annexin V/PI dual staining, with significance assessed by t-test or two-way ANOVA.</p><p><strong>Conclusions: </strong>PBRM1 loss confers selective hypersensitivity to PARP inhibitors, which intensify DNA-damage signaling, promote G2/M checkpoint arrest, trigger apoptosis, and induce stress-response genes such as CSRNP3. Although this effect appears context-dependent and was not observed uniformly across all PBRM1^-/- models tested. These results support further evaluation of PBRM1 as a potential predictive biomarker in defined molecular contexts rather than as a universal marker of PARP inhibitor sensitivity.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}